Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib
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Open Access
- 12 June 2014
- journal article
- research article
- Published by Massachusetts Medical Society in The New England Journal of Medicine
- Vol. 370 (24), 2286-2294
- https://doi.org/10.1056/nejmoa1400029
Abstract
Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (BTK) and is effective in chronic lymphocytic leukemia (CLL). Resistance to irreversible kinase inhibitors and resistance associated with BTK inhibition have not been characterized. Although only a small proportion of patients have had a relapse during ibrutinib therapy, an understanding of resistance mechanisms is important. We evaluated patients with relapsed disease to identify mutations that may mediate ibrutinib resistance. We performed whole-exome sequencing at baseline and the time of relapse on samples from six patients with acquired resistance to ibrutinib therapy. We then performed functional analysis of identified mutations. In addition, we performed Ion Torrent sequencing for identified resistance mutations on samples from nine patients with prolonged lymphocytosis. We identified a cysteine-to-serine mutation in BTK at the binding site of ibrutinib in five patients and identified three distinct mutations in PLCγ2 in two patients. Functional analysis showed that the C481S mutation of BTK results in a protein that is only reversibly inhibited by ibrutinib. The R665W and L845F mutations in PLCγ2 are both potentially gain-of-function mutations that lead to autonomous B-cell–receptor activity. These mutations were not found in any of the patients with prolonged lymphocytosis who were taking ibrutinib. Resistance to the irreversible BTK inhibitor ibrutinib often involves mutation of a cysteine residue where ibrutinib binding occurs. This finding, combined with two additional mutations in PLCγ2 that are immediately downstream of BTK, underscores the importance of the B-cell–receptor pathway in the mechanism of action of ibrutinib in CLL. (Funded by the National Cancer Institute and others.)Keywords
This publication has 32 references indexed in Scilit:
- A Hypermorphic Missense Mutation in PLCG2, Encoding Phospholipase Cγ2, Causes a Dominantly Inherited Autoinflammatory Disease with ImmunodeficiencyAmerican Journal of Human Genetics, 2012
- Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemiaNature, 2012
- SF3B1and Other Novel Cancer Genes in Chronic Lymphocytic LeukemiaThe New England Journal of Medicine, 2011
- Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765Blood, 2011
- Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemiaNature, 2011
- The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing dataGenome Research, 2010
- The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancyProceedings of the National Academy of Sciences of the United States of America, 2010
- Fast and accurate short read alignment with Burrows–Wheeler transformBioinformatics, 2009
- The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinibProceedings of the National Academy of Sciences of the United States of America, 2007
- Imatinib Compared with Interferon and Low-Dose Cytarabine for Newly Diagnosed Chronic-Phase Chronic Myeloid LeukemiaThe New England Journal of Medicine, 2003